Administrative Supplement to Immunologic, Inflammatory, and Clinical contributors to HIV-Related Heart Failure with Preserved Ejection Fraction

总结 本申请的目的是确定可能导致 人类免疫缺陷病毒（HIV）感染者射血分数正常的心力衰竭（HFpEF）， 其临床相关目标是改善HIV感染者的HFpEF筛查、预防和治疗 （威尔斯亲王医院）。HFpEF是一种具有高死亡率的复杂综合征：50%的HFpEF患者在5年内死亡， 诊断. HFpEF和舒张功能障碍（HFpEF基础的关键结构异常）的发生率为 艾滋病毒感染者的患病率明显高于没有感染艾滋病毒的人，最近的研究发现， 舒张功能障碍的PWH比没有艾滋病毒的人。一般来说，炎症和免疫功能障碍是 HFpEF的重要沉淀剂，可能对HIV相关HFpEF特别重要。但数据 关于PWH中HFpEF临床风险因素和病理生理学的研究有限。一个关键原因是 一个持续的科学差距是，没有大的，多样化的，多中心队列的PWH已裁定心力衰竭 事件或将这些事件与生物标本联系起来-这是准确表征和研究特定 心力衰竭的亚型我们建议在一个大型的现代队列中进行这项研究，该队列中有> 35，000名PWH临床护理人员 在整个美国;这个队列有一个广泛的个体相关的生物标本，病人， 报告的结果，以及获得大型艾滋病毒队列中独特的临床成像数据， 需要全面表征HIV中的HFpEF。我们的中心假设是，PWH与不完全 免疫恢复，如较低的CD 4计数和CD 4/CD 8比值所示，对HFpEF特别敏感 在存在从高血压到与脱靶相关的特定ART类别的“二次打击”的情况下， 合并症（如体重增加）。在第一个目标中，我们将调查临床风险因素和相互作用 其中，与PWH的HFpEF事件相关性最强。在第二个目标中，我们寻求更多 深入了解HIV相关HFpEF的生物学，因此将利用多标记蛋白质组学 我们在非HIV HFpEF患者中有广泛的初步数据， HFpEF对PWH的炎症贡献者。在目标3中，我们将使用一种新的方法来确定，在一个单一的- 细胞水平，免疫细胞基因表达的有意义差异可能导致全身性生物标志物 PWH的异常和HFpEF;我们将在目标4中验证心脏组织中的这些结果。我们有数据可以 支持每个目标的前提和可行性，我们的PI非常适合领导拟议的分析;作为 作为一名心脏病专家，他最近担任美国心脏协会关于艾滋病的科学声明的撰写主席 和CVD，这是一个里程碑式的文件，需要广泛的多学科协调。在PI的带领下，我们的团队 具有成功执行分析所需的方法和内容专业知识。通过完成 为了达到这个目的，我们打算获得关于HIV相关HF的关键临床和病理生理学知识 这将为PWH中HFpEF的预防、诊断和最终治疗提供信息。

SUMMARY The purpose of this application is to determine clinical, immunologic, and inflammatory factors that may lead to heart failure with preserved ejection fraction (HFpEF) for people with human immunodeficiency virus (HIV), with the clinically relevant goal of improving HFpEF screening, prevention, and therapy for people with HIV (PWH). HFpEF is a complex syndrome with high mortality: 50% of persons with HFpEF die within 5 years of diagnosis. Rates of HFpEF and diastolic dysfunction – the key structural abnormality underlying HFpEF – are significantly higher for PWH than people without HIV, with recent studies finding a 4-8-fold higher prevalence of diastolic dysfunction for PWH than people without HIV. In general, inflammation and immune dysfunction are important precipitants of HFpEF, and may be particularly important for HIV-associated HFpEF. However, data are limited regarding HFpEF clinical risk factors and pathophysiology in PWH. One key reason for this continued scientific gap is that no large, diverse, multi-center cohorts of PWH have adjudicated heart failure events or linked these to biospecimens – a necessary step to accurately characterize and investigate specific subtypes of heart failure. We propose to do this in a large, modern cohort of >35,000 PWH in clinical care throughout the United States; this cohort has an extensive array of individually-linked bio-specimens, patient- reported outcomes, and access to clinical imaging data that are unique among large HIV cohorts and necessary to comprehensively characterize HFpEF in HIV. Our central hypothesis is that PWH with incomplete immune recovery, as indicated by lower CD4 counts and CD4/CD8 ratios, are especially susceptible to HFpEF in the presence of “second hits” ranging from hypertension to specific ART classes associated with off-target comorbidities (such as weight gain). In the first aim, we will investigate clinical risk factors and interactions thereof which are most strongly associated with incident HFpEF for PWH. In the second aim, we seek to more deeply understand the biology of HIV-associated HFpEF and will therefore leverage a multi-marker proteomics panel – for which we have extensive pilot data in non-HIV HFpEF patients – to define immunologic and inflammatory contributors to HFpEF for PWH. In Aim 3, we will use a novel method to determine, at a single- cell level, meaningful differences in immune cell gene expression that may lead to systemic biomarker abnormalities and HFpEF for PWH; we will validate these findings in cardiac tissue in Aim 4. We have data to support the premise and feasibility of each aim, and our PI is ideally suited to lead the proposed analyses; as a cardiologist, he recently served as writing chair of the American Heart Association’s scientific statement on HIV and CVD, a landmark document that required extensive multidisciplinary coordination. Led by the PI, our team has the requisite methods and content expertise to successfully perform the analyses. Through completion of the aims, we intend to generate key clinical and pathophysiological knowledge regarding HIV-associated HF which will inform improved prevention, diagnosis, and ultimately treatment of HFpEF among PWH.